Endogenous opioid peptides have been postulated to modulate the neuropathogenesis of human immunodeficiency virus (HIV)-1, the etiologic agent of acquired immunodeficiency syndrome (AIDS) dementia. The principal hypothesis of the work proposed in this grant renewal application is that kappa opioids have a neuroprotective role in HIV-l-induced brain disease by suppressing HIV-1 expression and by reducing viral-induced neuronal injury. In the past several years, we have found that kappa opioid receptor (KOR) ligands inhibit HIV-1 expression in acutely infected human microglial cell cultures. In preliminary studies, KOR ligands also appear to suppress viral expression in cultures of human monocytes, the precursor cells of microglia. Although the mechanism of this antiviral effect has not yet been elucidated, kappa opioids are proposed to trigger a cascade of cellular events resulting in reduced viral expression by one or more of the following mechanisms: 1) inhibition of viral entry into target cells, 2) reduced activation of nuclear factor-kappaB, a cellular transcription factor required for the activation of the HIV-1 replication, 3) suppression of HIV-1 promoter activity, or 4) potentiation of the production of antiviral beta-chemokines by opioid-treated cells. Also, the anti-viral effects of U5O,488 will be tested using primary HIV-1 isolates (Specific Aim l). In addition to their antiviral activity, KOR ligands will be evaluated for their neuroprotective activity against HIV-1-induced toxicity using the HIV-l SF162 strain and primary isolates. The protective mechanism of KOR ligands is postulated to involve either l) an indirect mechanism by inhibiting microglial cell- and monocyte- induced production of neurotoxins (i.e., quinolinate, Tat, or cytokines [interleukin-1beta and tumor necrosis factor-alpha] or 2) a direct mechanism protecting neurons against toxicity induced by these toxins (Specific Aim 2). The findings from these studies will potentially provide insights into mechanisms associated with antiviral and neuroprotective effects of kappa opioids and hopefully will lead to development of new therapeutic approaches for AIDS dementia.